"Shy" Study Suggests New Treatment Mechanism

by John S. James

Summary: A study found that socially inhibited persons with HIV did much worse than others virologically -- due to biological differences that might be reversible with readily available drugs. This theory would be easy to test in small clinical trials. If it works, it might lead to a new kind of treatment that could greatly reduce viral load for some patients. [2003-12-28]

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A careful study of 54 asymptomatic, HIV-positive gay men, published December 15, 2003, in the journal Biological Psychiatry found that "socially inhibited" individuals had a viral load setpoint eight times higher than others -- and a much worse response to antiretroviral treatment as well, with only about one eighth of the viral load reduction of the other volunteers (all treated volunteers were starting HAART for the first time).(1) The study also showed that elevated activity of the autonomic nervous system explained most of this difference - - showing "the first clinical evidence that differential neuronal activity mediates relationships between psychological risk factors and infectious disease pathogenesis" (quotation from the abstract). Apparently socially inhibited persons have a higher baseline stress level, and control excess stress by limiting social interaction.

The authors note other studies showing that norepinephrine, which is released in response to stress, changes the function of cells in several ways that result in faster HIV replication. They note that naturally occurring differences in autonomic nervous system activity can be associated with up to a 100-fold difference in HIV viral load -- and suggest testing drugs that might become powerful adjunctive therapies, slowing HIV progression and greatly improving antiretroviral treatment in many patients.

A recent article in The Washington Post discussed this work, and related work of other scientists.(2) For example, a link between depression and HIV progression may be mediated by different biochemical pathways -- opening doors to different treatments for depressed patients than for those with a high stress level.

Comment: Designing Clinical Trials

There are already approved drugs, widely used for other purposes, that can reduce some of the mechanisms that may be responsible for poor control of HIV and poor response to antiretrovirals in certain patients. But until recently, nobody had any reason to imagine using them as part of a strategy for reducing HIV viral load. (For example, beta-blockers are used to lower effects of norepinephrine. But the link with depression might lead to entirely different drug candidates, for to different patients.)

Once plausible drugs are identified, they could be tested relatively easily, because viral load is a continuous measurement that reaches a new setpoint fairly rapidly. For example, one might select patients who are poorly controlling HIV (so that they have a large scope for improvement), who meet other criteria such as social inhibition suggesting that the drug being tested might work particularly well (so that success is easy to see), and who also have a fairly stable viral load, either on treatment or off (so that changes can more easily be attributed to the drug being tested). These patients would be randomized to either take the drug immediately or wait a few weeks; in either case their viral load would be carefully monitored for several weeks or months. If the drug worked as hoped, there would be a large decrease in viral load without any other change in antiretroviral treatment. If this happened, the volunteers would be followed indefinitely to see if the treatment could be continued successfully. These trials would only require a few patients each. They could be designed, recruited, and conducted in months, not years.

It is likely that drug candidates can be found that are already widely available and well known in human use. Some of them may be inexpensive. Often manufacturers of non-HIV drugs do not want an HIV use discovered (because they fear that patients, or their family members or friends, will wrongly suspect that someone is secretly being treated for AIDS -- threatening a large market for a much smaller one). But if a drug is already in widespread use, the manufacturer's cooperation in researching it, while helpful, would not be necessary. The community will need to pay attention, however, and take initiative to make things happen. The system cannot be trusted to work by itself.

At a time when progress in conventional antiretroviral treatment has slowed, here is a wide-open area that, if it works, could rapidly lead to major treatment advances.

References

(1) Cole SW, Kemeny ME, Fahey JL, Zack JA, and Naliboff BD. Psychological risk factors for HIV pathogenesis: Mediation by the autonomic nervous system. Biological Psychiatry December 15, 2003; volume 54, pages 1444-1456.

(2) "Stress Found to Weaken Resistance to Illness" by Shankar Vedantam, Washington Post, December 22, 2003, page A12.

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